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Abstract Background Patients with COPD are often affected by loss of bone mineral density (BMD) and osteoporotic fractures. Natriuretic peptides (NP) are known as cardiac markers, but have also been linked to fragility-associated fractures in the elderly. As their functions include regulation of fluid and mineral balance, they also might affect bone metabolism, particularly in systemic disorders such as COPD. Research question We investigated the association between NP serum levels, vertebral fractures and BMD assessed by chest computed tomography (CT) in patients with COPD. Methods Participants of the COSYCONET cohort with CT scans were included. Mean vertebral bone density on CT (BMD-CT) as a risk factor for osteoporosis was assessed at the level of TH12 (AI-Rad Companion), and vertebral compression fractures were visually quantified by two readers. Their relationship with N-terminal pro-B-type natriuretic peptide (NT-proBNP), Mid-regional pro-atrial natriuretic peptide (MRproANP) and Midregional pro-adrenomedullin (MRproADM) was determined using group comparisons and multivariable analyses. Results Among 418 participants (58% male, median age 64 years, FEV1 59.6% predicted), vertebral fractures in TH12 were found in 76 patients (18.1%). Compared to patients without fractures, these had elevated serum levels (p ≤ 0.005) of MRproANP and MRproADM. Using optimal cut-off values in multiple logistic regression analyses, MRproANP levels ≥ 65 nmol/l (OR 2.34; p = 0.011) and age (p = 0.009) were the only significant predictors of fractures after adjustment for sex, BMI, smoking status, FEV1% predicted, SGRQ Activity score, daily physical activity, oral corticosteroids, the diagnosis of cardiac disease, and renal impairment. Correspondingly, MRproANP (p

Abstract Background Reference values for lung volumes are necessary to identify and diagnose restrictive lung diseases and hyperinflation, but the values have to be validated in the relevant population. Our aim was to investigate the Global Lung Function Initiative (GLI) reference equations in a representative healthy Austrian population and create population-derived reference equations if poor fit was observed. Methods We analysed spirometry and body plethysmography data from 5371 respiratory healthy subjects (6–80 years) from the Austrian LEAD Study. Fit with the GLI equations was examined using z-scores and distributions within the limits of normality. LEAD reference equations were then created using the LMS method and the generalized additive model of location shape and scale package according to GLI models. Results Good fit, defined as mean z-scores between + 0.5 and -0.5,was not observed for the GLI static lung volume equations, with mean z-scores > 0.5 for residual volume (RV), RV/TLC (total lung capacity) and TLC in both sexes, and for expiratory reserve volume (ERV) and inspiratory capacity in females. Distribution within the limits of normality were shifted to the upper limit except for ERV. Population-derived reference equations from the LEAD cohort showed superior fit for lung volumes and provided reproducible results. Conclusion GLI lung volume reference equations demonstrated a poor fit for our cohort, especially in females. Therefore a new set of Austrian reference equations for static lung volumes was developed, that can be applied to both children and adults (6–80 years of age).

Evaluating variability and stability using measures for nonlinear dynamics may provide additional insight into the structure of the locomotor system, reflecting the neuromuscular system's organization of gait. This is in particular of interest when this system is affected by a respiratory disease and it's extrapulmonary manifestations. This study assessed stride-to-stride fluctuations and gait stability in patients with chronic obstructive pulmonary disease (COPD) during a self-paced, treadmill 6-minute walk test (6MWT) and its association with clinical outcomes. In this cross-sectional study, eighty patients with COPD (age 62±7y; forced expiratory volume in first second 56±19%predicted) and 39 healthy older adults (62±7y) were analyzed. Gait parameters including stride-to-stride fluctuations (coefficient of variation (CoV), predictability (sample entropy) and stability (Local Divergence Exponent (LDE)) were calculated over spatiotemporal parameters and center of mass velocity. Independent t-test, Mann-Whitney U test and ANCOVA analyses were conducted. Correlations were calculated between gait parameters, functional mobility using Timed Up and Go Test, and quadriceps muscle strength using dynamometry. Patients walked slower than healthy older adults. After correction for Speed, patients demonstrated increased CoV in stride length (F(1,116) = 5.658, p = 0.019), and increased stride length predictability (F(1,116) = 3.959, p = 0.049). Moderate correlations were found between mediolateral center of mass velocity LDE and normalized maximum peak torque (ρ = -0.549). This study showed that patients with COPD demonstrate alterations in stride length fluctuations even when adjusted for walking speed, highlighting the potential of nonlinear measures to detect alterations in gait function in patients with COPD. Association with clinical outcomes were moderate to weak, indicating that these clinical test are less discriminative for gait alterations.

Rationale Structural airway changes related to chronic cough (CC) are described in the literature, but so far reported data are rare and non-conclusive. Furthermore, they derive mainly from cohorts with small sample sizes. Advanced CT imaging not only allows airway abnormalities to be quantified, but also to count the number of visible airways. The current study evaluates these airway abnormalities in CC and assesses the contribution of CC in addition to CT findings on the progression of airflow limitation, defined as a decline in forced expiratory volume in 1 s (FEV1) over time.Methods A total of 1183 males and females aged ≥40 years with thoracic CT scans and valid spirometry from Canadian Obstructive Lung Disease, a Canadian multicentre, population-based study has been included in this analysis. Participants were stratified into 286 never-smokers, 297 ever-smokers with normal lung function and 600 with chronic obstructive pulmonary disease (COPD) of different severity grades. Imaging parameters analyses included total airway count (TAC), airway wall thickness, emphysema as well as parameters for functional small airway disease quantification.Results Irrespective of COPD presence, CC was not related to specific airway and lung structure features. Independent of TAC and emphysema score, CC was highly associated with FEV1 decline over time in the entire study population, particularly in ever-smokers (p

Abstract Background Spirometric small airways obstruction (SAO) is common in the general population. Whether spirometric SAO is associated with respiratory symptoms, cardiometabolic diseases, and quality of life (QoL) is unknown. Methods Using data from the Burden of Obstructive Lung Disease study (N = 21,594), we defined spirometric SAO as the mean forced expiratory flow rate between 25 and 75% of the FVC (FEF25-75) less than the lower limit of normal (LLN) or the forced expiratory volume in 3 s to FVC ratio (FEV3/FVC) less than the LLN. We analysed data on respiratory symptoms, cardiometabolic diseases, and QoL collected using standardised questionnaires. We assessed the associations with spirometric SAO using multivariable regression models, and pooled site estimates using random effects meta-analysis. We conducted identical analyses for isolated spirometric SAO (i.e. with FEV1/FVC ≥ LLN). Results Almost a fifth of the participants had spirometric SAO (19% for FEF25-75; 17% for FEV3/FVC). Using FEF25-75, spirometric SAO was associated with dyspnoea (OR = 2.16, 95% CI 1.77–2.70), chronic cough (OR = 2.56, 95% CI 2.08–3.15), chronic phlegm (OR = 2.29, 95% CI 1.77–4.05), wheeze (OR = 2.87, 95% CI 2.50–3.40) and cardiovascular disease (OR = 1.30, 95% CI 1.11–1.52), but not hypertension or diabetes. Spirometric SAO was associated with worse physical and mental QoL. These associations were similar for FEV3/FVC. Isolated spirometric SAO (10% for FEF25-75; 6% for FEV3/FVC), was also associated with respiratory symptoms and cardiovascular disease. Conclusion Spirometric SAO is associated with respiratory symptoms, cardiovascular disease, and QoL. Consideration should be given to the measurement of FEF25-75 and FEV3/FVC, in addition to traditional spirometry parameters.

Background: The use of maintenance medication in patients with chronic obstructive pulmonary disease (COPD) in real life is known to deviate from recommendations in guidelines, which are largely based on randomized controlled trials and selected populations. Objectives: We used the COSYCONET ( CO PD and Sy stemic Consequences – Co morbidities Net work) cohort to analyze factors linked to the use of COPD drugs under non-interventional circumstances. Design: COSYCONET is an ongoing, multi-center, non-interventional cohort of patients with COPD. Methods: Patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 0–4 participating in visits 1–5 were included. Data covered the period from 2010 to 2018. Generalized linear models were used to examine the relation of COPD characteristics to different types of respiratory medication. Results: A total of 1043 patients were included. The duration of observation was 4.5 years. Use of respiratory medication depended on GOLD grades 0–4 and groups A-D. Long-acting muscarinic antagonist therapy increased over time, and was associated with low carbon monoxide (CO) diffusing capacity, while inhaled corticosteroid (ICS) use decreased. Active smoking was associated with less maintenance therapy in general, and female sex with less ICS use. From the eight items of the COPD Assessment Test, only hill and stair climbing were consistently linked to treatment. Conclusion: Using data from a large, close to real-life observational cohort, we identified factors linked to the use of various types of respiratory COPD medication. Overall, use was consistent with GOLD recommendations. Beyond this, we identified other correlates of medication use that may help us to understand and improve therapy decisions in clinical practice. Trial registration: ClinicalTrials.gov NCT01245933.

Abstract In chronic obstructive pulmonary disease (COPD), comorbidities and worse functional status predict worse outcomes, but how these predictors compare with regard to different outcomes is not well studied. We thus compared the role of cardiovascular comorbidities for mortality and exacerbations. Data from baseline and up to four follow-up visits of the COSYCONET cohort were used. Cox or Poisson regression was employed to determine the relationship of predictors to mortality or mean annual exacerbation rate, respectively. Predictors comprised major comorbidities (including cardiovascular disease), lung function (forced expiratory volume in 1 s [FEV1], diffusion capacity for carbon monoxide [TLCO]) and their changes over time, baseline symptoms, exacerbations, physical activity, and cardiovascular medication. Overall, 1817 patients were included. Chronic coronary artery disease (p = 0.005), hypertension (p = 0.044) and the annual decline in TLCO (p = 0.001), but not FEV1 decline, were predictors of mortality. In contrast, the annual decline of FEV1 (p = 0.019) but not that of TLCO or cardiovascular comorbidities were linked to annual exacerbation rate. In conclusion, the presence of chronic coronary artery disease and hypertension were predictors of increased mortality in COPD, but not of increased exacerbation risk. This emphasizes the need for broad diagnostic workup in COPD, including the assessment of cardiovascular comorbidity. Clinical Trials: NCT01245933.

Abstract Background Whether restricted spirometry, i.e. low Forced Vital Capacity (FVC), predicts chronic cardiometabolic disease is not definitely known. In this international population-based study, we assessed the relationship between restricted spirometry and cardiometabolic comorbidities. Methods A total of 23,623 subjects (47.5% males, 19.0% current smokers, age: 55.1 ± 10.8 years) from five continents (33 sites in 29 countries) participating in the Burden of Obstructive Lung Disease (BOLD) study were included. Restricted spirometry was defined as post-bronchodilator FVC

Abstract We analyzed SARS-CoV-2 seroprevalence in a large, well-described representative Viennese cohort after an early governmental lockdown with respect to the occurrence of symptoms and household transmission. Participants of the LEAD Study, a population-based cohort study from Vienna, Austria, were invited along with their household members (April 20th to May20th 2020). Sera were analyzed using anti-SARS-CoV-2 immunoassay including a neutralization test as a confirmatory assay. A total of 12,419 individuals participated (5984 LEAD participants; 6435 household members), 163 (1.31%; 59 LEAD cohort members) of whom were SARS-CoV-2 antibody positive. The estimated number of COVID-19 cases projected from our findings by age and sex for Vienna was 21,504 (1.13%). Cumulative number of positively tested cases in Vienna until May 20th 2020 was 3020, hence 7.1 times (95% confidence interval 5.5–9.1) lower than projected. Relative risk (RR) of seropositivity by age was highest for children aged 6–9 years [RR compared to age group 20–49: 1.21 (CI 0.37–4.01)], lowest for ≥ 65 years [RR 0.47 (CI 0.21–1.03)]. Half of the positive individuals developed no or mild symptoms. In a multivariate analysis, taste and smell disturbances were most strongly related to SARS-CoV-2 positivity. Infection probability within households with one confirmed SARS-CoV-2-specific antibody-positive person was 31%. Although seroprevalence was very low (1.13%) for a central European capital city, due to an early governmental lockdown, SARS-CoV-2 infections were more prevalent than officially reported polymerase chain reaction-positive cases. Of note, seroprevalence was highest in young children. Half of SARS-CoV-2 antibody-positive subjects had no or only mild symptoms. Taste and smell disturbances were most prominent, possibly guiding clinicians in diagnosing SARS-CoV-2 infection.

Abstract Background Cut offs for fat-free mass index (FFMI) and appendicular skeletal muscle mass index (ASMI) are available for diagnosing low muscle mass in patients with COPD. This study aimed to investigate: (1) the frequency of low muscle mass (FFMI and ASMI) applying different cut-offs and (2) the functional translation (clinical impact) of low muscle mass, in patients with COPD stratified into BMI categories. Methods Patients with COPD were assessed regarding body composition, exercise capacity, quadriceps muscle strength, symptoms of anxiety and depression, dyspnea and quality of life upon referral to pulmonary rehabilitation. The proportion of patients with low muscle mass was compared among BMI categories. Clinical outcomes between patients with normal and low muscle mass within each BMI category were compared. Results 469 patients with COPD were included for analyses. The frequency of patients classified as low FFMI varied significantly according to the choice of cut-off (32 to 54%; P

Abstract Background Over the years, the scope of outcomes assessment in chronic obstructive pulmonary disease (COPD) has broadened, allowing for the evaluation of various patient-reported outcomes (PROs). As it still remains unclear whether and to what extent PROs mirror the exercise performance of patients with COPD, the current study aimed to assess the association between different exercise test outcomes and PROs, before and after pulmonary rehabilitation (PR). Methods Correlations between PROs used to describe health-related quality of life (HRQoL), mood status, level of care dependency and dyspnea in patients with COPD and commonly used laboratory- and field-based exercise test outcomes were evaluated in 518 individuals with COPD attending PR. Results Overall, correlations between PROs and exercise test outcomes at baseline were statistically significant. The correlation between modified Medical Research Council (mMRC) dyspnea score and 6-min walking distance (6MWD) was strongest (ρ:-0.65; p

Abstract Introduction Cachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers. Methods We analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) ( 5% in the past 12 months or low BMI and 3/5 criteria: decreased muscle strength, anorexia, abnormal biochemistry (anemia or high c-reactive protein (> 5 mg/l)), fatigue, and low FFMI. Differential gene expression was assessed between cachectic and non-cachectic subjects, adjusting for age, sex, white blood cell counts, and technical covariates. Gene set enrichment analysis was performed using MSigDB. Results The prevalence of COPD cachexia was 13.7% in COPDGene and 7.9% in ECLIPSE. Fourteen genes were differentially downregulated in cachectic versus non-cachectic COPD patients in COPDGene (FDR

Background Clusters of COPD patients have been reported in order to individualize the treatment program. Neither co-morbidity clusters, nor integrated respiratory physiomics clusters contributed to a better prediction of outcomes. Based on a thoroughly assessed set of pulmonary and extra-pulmonary traits at the start of a pulmonary rehabilitation (PR) program, we recently described seven clusters of COPD patients. The aims of this study are to confirm multidimensional differential response and to assess the potential of pulmonary and extra-pulmonary traits-based clusters to predict this multidimensional response to PR pulmonary in COPD patients. Methods Outcomes of a 40-session PR program for COPD patients, referred by a chest physician, were evaluated based on the minimal clinically important difference (MCID) for 6-minute walk distance (6MWD), cycle endurance time, Canadian Occupational Performance Measure performance and satisfaction scores, Hospital Anxiety and Depression Scale anxiety and depression scores, MRC dyspnea grade and St George’s Respiratory Questionnaire. The aforementioned response indicators were used to calculate the overall multidimensional response and patients were grouped in very good, good, moderate and poor responders. In the same way, responses to pulmonary rehabilitation were compared based on seven previously identified pulmonary and extra-pulmonary traits-based clusters. Results Of the whole sample, drop out was 19% and 419 patients (55.4% males, age: 64.3 ± 8.8, FEV1% of predicted: 48.9 ± 20) completed the pulmonary rehabilitation program. Very good responders had significantly worse baseline characteristics with a higher burden of disease, a higher proportion of rollator-users, higher body mass index (BMI), more limitations of activities in daily life, emotional dysfunction, higher symptoms of dyspnea and worse quality of life. Of the seven pre-identified clusters, ‘the overall best functioning cluster’ and ‘the low disease burden cluster’ both including the best 6MWD, the lowest dyspnea score and the overall best health status, demonstrated attenuated outcomes, while in ‘the cluster of disabled patients’, 76% of the patients improved health status with at least 2 times MCID. This ‘cluster of disabled patients’ as well as ‘the multimorbid cluster’, ‘the emotionally dysfunctioning cluster’, ‘the overall worst-functioning cluster’ and ‘the physically dysfunctioning cluster’ all demonstrated improvements in performance and satisfaction for occupational activities (more than 65% of patients improved with > 1MCID), emotional functioning (more than 50% of patients improved with > 1 MCID) and overall health status (more than 58%). Conclusion The current study confirms the differential response to pulmonary rehabilitation based on multidimensional response profiling. Cluster analysis of baseline traits illustrates that non-linear, clinically important differences can be achieved in the most functionally and emotionally impaired clusters and that ‘the overall best functional cluster’ as well as ‘the low disease burden cluster’ had an attenuated outcome.

As part of an individualized intervention to improve the physical, emotional, and social functioning of patients with chronic respiratory diseases in general and chronic obstructive pulmonary disease in particular, awareness of the presence and consequences of changes in body composition increased enormously during the last decades, and nutritional intervention is considered as an essential component in the comprehensive approach of these patients. This review describes the prevalence and the clinical impact of body composition changes and also provides an update of current intervention strategies. It is argued that body composition, preferentially a three-component evaluation of fat, lean, and bone mass, must become part of a thorough assessment of every patient, admitted for pulmonary rehabilitation.

Abstract Background Cachexia is associated with increased mortality risk among chronic obstructive pulmonary disease (COPD) patients. However, low body mass index (BMI) as opposed to cachexia is often used, particularly when calculating the BODE (BMI, Obstruction, Dyspnea and Exercise) index. For this reason, we examined mortality using a consensus definition and a weight-loss definition of cachexia among COPD cases and compared two new COPD severity indices with BODE. Methods In the current report, the consensus definition for cachexia incorporated weight-loss > 5% in 12-months or low BMI in addition to 3/5 of decreased muscle strength, fatigue, anorexia, low FFMI and inflammation. The weight-loss definition incorporated weight-loss > 5% or weight-loss > 2% (if low BMI) in 12-months. The low BMI component in BODE was replaced with the consensus definition to create the CODE (Consensus cachexia, Obstruction, Dyspnea and Exercise) index and the weight-loss definition to create the WODE (Weight loss, Obstruction, Dyspnea and Exercise) index. Mortality was assessed using Kaplan-Meier survival and Cox Regression. Performance of models was compared using C-statistics. Results Among 1483 COPD cases, the prevalences of cachexia by the consensus and weight-loss definitions were 4.7 and 10.4%, respectively. Cachectic patients had a greater than three-fold increased mortality by either the consensus or the weight-loss definition of cachexia independent of BMI and lung function. The CODE index predicted mortality slightly more accurately than the BODE and WODE indices. Conclusions Cachexia is associated with increased mortality among COPD patients. Monitoring cachexia using weight-loss criteria is relatively simple and predictive of mortality among COPD cases who may be missed if only low BMI is used.

Abstract Background Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with loss of lung function and poor outcomes for patients. However, there are limited data on the time course of changes in forced expiratory volume in 1 s (FEV1) preceding the first reported symptom and after the start of an exacerbation. Methods WISDOM was a multinational, randomized, double-blind, active-controlled, 52-week study in patients with severe-to-very severe COPD. Patients received triple therapy (long-acting muscarinic antagonist and long-acting β2-agonist/inhaled corticosteroid [ICS]) for 6 weeks, and were randomized to continue triple therapy or stepwise withdrawal of the ICS (dual bronchodilator group). After suitable training, patients performed daily spirometry at home using a portable, battery-operated spirometer. In the present post hoc analysis, patients who continued to perform daily home spirometry and completed at least one measurement per week for a 56-day period before and after the start of a moderate or severe exacerbation were included. Missing values were imputed by linear interpolation (intermittent), backfilling (beginning) or carry forward (end). Exacerbation onset was the first day of a reported symptom of exacerbation. Results Eight hundred and eighty-eight patients in the WISDOM study had a moderate/severe exacerbation after the complete ICS withdrawal visit; 360 of them contributed at least one FEV1 measure per week for the 8 weeks before and after the event and are included in this analysis. Mean daily FEV1 began to decline from approximately 2 weeks before the onset of symptoms of an exacerbation, dropping from 0.907 L (mean Days − 56 to − 36 before the exacerbation) to 0.860 L on the first day of the exacerbation. After the exacerbation, mean FEV1 improved but did not return to pre-exacerbation levels (mean Days 36–56 after the exacerbation, 0.875 L). The pattern of FEV1 changes around exacerbations was similar in the triple therapy and dual bronchodilator groups, and a similar pattern was seen in moderate and severe exacerbations when analysed separately. Conclusions Mean lung function starts to decline prior to the first reported symptoms of an exacerbation, and does not recover to pre-exacerbation levels 8 weeks after the event. Trial registration WISDOM (ClinicalTrials.gov number, NCT00975195).

Abstract Background The COPD Assessment Test (CAT) contains eight items (cough, phlegm, chest tightness, breathlessness, limited activities, confidence leaving home, sleeplessness and energy). The current study aimed 1) to better understand the impact of the respiratory and non-respiratory CAT item scores on the CAT total score; and 2) to determine the impact of pulmonary rehabilitation (PR) on CAT items and CAT total score. Methods CAT total score of ≥10 or ≥ 18 points was used to classify patients as highly symptomatic, a decrease of 2 points was considered as clinically relevant improvement. ‘Cough’, ‘phlegm’, ‘chest tightness’, ‘breathlessness’ were defined as respiratory items; ≥3 points on each item was defined as highly symptomatic. Results In total, 497 clinically stable patients (55% male, age 64.0 (57.5–71.0) years, FEV1 46.0 (32.0–63.0)% predicted, CAT total score 22.0 (17.5–26.0) points) were included. 95% had CAT score ≥ 10 points and 75% ≥18 points. Respectively, 45% and 54% of subjects scored high on 3 or 4 of the respiratory CAT items. Following PR, 220 patients (57.7%) reported an improved health status as assessed by CAT total score (− 3.0 (− 7.0–1.0) points). Change in CAT item scores ranged from 0.0 (− 1.0–0.0) to − 1.0 (− 2.0–0.0) points) with best improvements in ‘energy’ (− 1.0 (− 2.0–0.0)points). Conclusions A substantial number of patients classified as highly symptomatic did not report a high level of respiratory symptoms, indicating that non-respiratory symptoms impact on disease classification and treatment algorithm. The impact of PR on CAT item scores varied by individual item. Trial registration Netherlands National Trial Register (NTR3416). Registered 2 May 2012.

Airway epithelial cells secrete extracellular vesicles (EVs) under basal conditions and when exposed to cigarette smoke extract (CSE). Getting insights into the composition of these EVs will help unravel their functions in homeostasis and smoking-induced pathology. Here, we characterized the proteomic composition of basal and CSE-induced airway epithelial EVs. BEAS-2B cells were left unexposed or exposed to 1% CSE for 24 h, followed by EV isolation using ultrafiltration and size exclusion chromatography. Isolated EVs were labelled with tandem mass tags and their proteomic composition was determined using nano-LC-MS/MS. Tissue factor (TF) activity was determined by a factor Xa generation assay, phosphatidylserine (PS) content by prothrombinase assay and thrombin generation using calibrated automated thrombogram (CAT). Nano-LC-MS/MS identified 585 EV-associated proteins with high confidence. Of these, 201 were differentially expressed in the CSE-EVs according to the moderated t-test, followed by false discovery rate (FDR) adjustment with the FDR threshold set to 0.1. Functional enrichment analysis revealed that 24 proteins of the pathway haemostasis were significantly up-regulated in CSE-EVs, including TF. Increased TF expression on CSE-EVs was confirmed by bead-based flow cytometry and was associated with increased TF activity. CSE-EVs caused faster and more thrombin generation in normal human plasma than control-EVs, which was partly TF-, but also PS-dependent. In conclusion, proteomic analysis allowed us to predict procoagulant properties of CSE-EVs which were confirmed in vitro. Cigarette smoke-induced EVs may contribute to the increased cardiovascular and respiratory risk observed in smokers.

With a rapidly growing elderly human population, the incidence of age-related lung diseases such as chronic obstructive pulmonary disease (COPD) continues to rise. It is widely believed that reactive oxygen species (ROS) play an important role in ageing and in age-related disease, and approaches of antioxidant supplementation have been touted as useful strategies to mitigate age-related disease progression, although success of such strategies has been very limited to date. Involvement of ROS in ageing is largely attributed to mitochondrial dysfunction and impaired adaptive antioxidant responses. NADPH oxidase (NOX) enzymes represent an important enzyme family that generates ROS in a regulated fashion for purposes of oxidative host defense and redox-based signalling, however, the associations of NOX enzymes with lung ageing or age-related lung disease have to date only been minimally addressed. The present review will focus on our current understanding of the impact of ageing on NOX biology and its consequences for age-related lung disease, particularly COPD, and will also discuss the implications of altered NOX biology for current and future antioxidant-based strategies aimed at treating these diseases.

The impact of body composition on the early origin of chronic diseases is an increasingly appreciated phenomenon. Little is known about the characteristics of children with varying body composition. The aim of this study was to investigate serum lipid profiles and other characteristics in relation to body composition. The data of 1394 participants (aged 6 to

Abstract Cardiovascular diseases are prevalent in patients with chronic obstructive pulmonary disease (COPD). Their coexistence implies that many COPD patients require anticoagulation therapy. Although more and more replaced by direct oral anticoagulants, vitamin K antagonists (VKAs) are still widely used. VKAs induce profound deficiency of vitamin K, a key activator in the coagulation pathway. It is recognized however that vitamin K is also an essential cofactor in the activation of other extrahepatic proteins, such as matrix Gla protein (MGP), a potent inhibitor of arterial calcification. No or insufficient MGP activation by the use of VKAs is associated with a rapid progression of vascular calcification, which may enhance the risk for overt cardiovascular disease. Vitamin K consumption, on the other hand, seems to have a protective effect on the mineralization of arteries. Furthermore, vascular calcification mutually relates to elastin degradation, which is accelerated in patients with COPD associating with impaired survival. In this commentary, we hypothesize that vitamin K is a critical determinant to the rate of elastin degradation. We speculate on the potential link between poor vitamin K status and crucial mechanisms of COPD pathogenesis and raise concerns about the use of VKAs in patients with this disease. Future intervention studies are needed to explore if vitamin K supplementation is able to reduce elastin degradation and vascular calcification in COPD patients.

Abstract Background Although proxies of patients with chronic obstructive pulmonary disease (COPD) need health-related knowledge to support patients in managing their disease, their current level of knowledge remains unknown. We aimed to compare health-related knowledge (generic and COPD-related knowledge) between patients with COPD and their resident proxies. Methods In this cross-sectional study, we included stable patients with moderate to very severe COPD and their resident proxies (n = 194 couples). Thirty-four statements about generic health and COPD-related topics were assessed in patients and proxies separately. Statements could be answered by ‘true’, ‘false’, or ‘do not know’. This study is approved by the Medical Research Ethics Committees United (MEC-U), the Netherlands (NL42721.060.12/M12–1280). Results Patients answered on average 17% of the statements incorrect, and 19% with ‘do not know’. The same figure (19%) for the incorrect and unknown statements was shown by proxies. Patients who attended pulmonary rehabilitation previously answered more statements correct (about three) compared to patients who did not attend pulmonary rehabilitation. More correct answers were reported by: younger patients, patients with a higher level of education, patients who previously participated in pulmonary rehabilitation, patients with better cognitive functioning, and patients with a COPD diagnosis longer ago. Conclusions Proxies of patients with COPD as well as patients themselves answer about two third of 34 knowledge statements about COPD correct. So, both patients and proxies seem to have an incomplete knowledge about COPD and general health. Therefore, education about general health and COPD should be offered to all subgroups of patients with COPD and their proxies. Trial registration This study is registered in the Dutch Trial Register ( NTR3941 ). Registered 19 April 2013.

Background: The objective of this study was to compare fatigue levels between subjects with and without COPD, and to investigate the relationship between fatigue, demographics, clinical features and disease severity. Methods: A total of 1290 patients with COPD [age 65 ± 9 years, 61% male, forced expiratory volume in 1 s (FEV1) 56 ± 19% predicted] and 199 subjects without COPD (age 63 ± 9 years, 51% male, FEV1 112 ± 21% predicted) were assessed for fatigue (Checklist Individual Strength-Fatigue), demographics, clinical features and disease severity. Results: Patients with COPD had a higher mean fatigue score, and a higher proportion of severe fatigue (CIS-Fatigue score 35 ± 12 versus 21 ± 11 points, p

BACKGROUND:While spirometry and particularly airflow limitation is still considered as an important tool in therapeutic decision making, it poorly reflects the heterogeneity of respiratory impairment in chronic obstructive pulmonary disease (COPD). The aims of this study were to identify pathophysiological clusters in COPD based on an integrated set of standard lung function attributes and to investigate whether these clusters can predict patient-related outcomes and differ in clinical characteristics. METHODS:Clinically stable COPD patients referred for pulmonary rehabilitation underwent an integrated assessment including clinical characteristics, dyspnea score, exercise performance, mood and health status, and lung function measurements (post-bronchodilator spirometry, body plethysmography, diffusing capacity, mouth pressures and arterial blood gases). Self-organizing maps were used to generate lung function based clusters. RESULTS:Clustering of lung function attributes of 518 patients with mild to very severe COPD identified seven different lung function clusters. Cluster 1 includes patients with better lung function attributes compared to the other clusters. Airflow limitation is attenuated in clusters 1 to 4 but more pronounced in clusters 5 to 7. Static hyperinflation is more dominant in clusters 5 to 7. A different pattern occurs for carbon monoxide diffusing capacity, mouth pressures and for arterial blood gases. Related to the different lung function profiles, clusters 1 and 4 demonstrate the best functional performance and health status while this is worst for clusters 6 and 7. All clusters show differences in dyspnea score, proportion of men/women, age, number of exacerbations and hospitalizations, proportion of patients using long-term oxygen and number of comorbidities. CONCLUSION:Based on an integrated assessment of lung function variables, seven pathophysiological clusters can be identified in COPD patients. These clusters poorly predict functional performance and health status.

Overground gait assessment is limited by the analysis of multiple strides or both spatiotemporal gait characteristics, while fixed speed treadmill walking restricts natural gait speed variations. The Gait Real-time Analysis Interactive Lab (GRAIL)-based 6-minute walk test (6MWT) enables 3D motion analysis and self-paced treadmill walking, and could provide insight in gait alterations in patients with chronic obstructive pulmonary disease (COPD). The aim of this study is to compare spatiotemporal gait characteristics between patients with COPD and healthy elderly during the GRAIL-based 6MWT.Eighty COPD patients (60% male; 62±7 years; FEV1:56±19% predicted) and 38 healthy elderly (63% male; 62±6 years; FEV1:119±17% predicted) performed two GRAIL-based 6MWTs. Mean differences and coefficient of variation of spatiotemporal gait characteristics were calculated using the trial with the largest walk distance. Sub-analyses were conducted to account for walking speed differences between groups, and muscle strength and COPD severity within the patient group.COPD patients showed increased temporal gait characteristics, decreased stride and step lengths, and increased gait variability compared to healthy elderly (p

Oxygen uptake (VO2) kinetics provide information about the ability to respond to the increased physical load during a constant work rate test (CWRT). Box-Jenkins transfer function (BJ-TF) models can extract kinetic features from the phase II VO2 response during a CWRT, without being affected by unwanted noise contributions (e.g., phase I contribution or measurement noise). CWRT data of 18 COPD patients were used to compare model fits and kinetic feature values between BJ-TF models and three typically applied exponential modelling methods. Autocorrelation tests and normalised root-mean-squared error values (BJ-TF: 2.8 ± 1.3%; exponential methods A, B and C: 10.5 ± 5.8%, 11.3 ± 5.2% and 12.1 ± 7.0%; p < 0.05) showed that BJ-TF models, in contrast to exponential models, could account for the most important noise contributions. This led to more reliable kinetic feature values compared to methods A and B (e.g., mean response time (MRT), BJ-TF: 74 ± 20 s; methods A-B: 100 ± 56 s−88 ± 52 s; p < 0.05). Only exponential modelling method C provided kinetic feature values comparable to BJ-TF features values (e.g., MRT: 75 ± 20 s). Based on theoretical considerations, we recommend using BJ-TF models, rather than exponential models, for reliable determinations of VO2 kinetics.

The 6-minute walk test (6MWT) in a regular hallway is commonly used to assess functional exercise capacity in patients with chronic obstructive pulmonary disease (COPD). However, treadmill walking might provide additional advantages over overground walking, especially if virtual reality and self-paced treadmill walking are combined. Therefore, this study aimed to assess the reproducibility and validity of the 6MWT using the Gait Real-time Analysis Interactive Lab (GRAIL) in patients with COPD and healthy elderly.Sixty-one patients with COPD and 48 healthy elderly performed two 6MWTs on the GRAIL. Patients performed two overground 6MWTs and healthy elderly performed one overground test. Differences between consecutive 6MWTs and the test conditions (GRAIL vs. overground) were analysed. Patients walked further in the second overground test (24.8 m, 95% CI 15.2-34.4 m, p

BACKGROUND: The prevalence of metabolic syndrome in COPD patients and its impact on patient related outcomes has been little studied. We evaluated the prevalence of metabolic syndrome and clinical and functional characteristics in patients with COPD and healthy subjects. METHODS: 228 COPD patients and 156 healthy subjects were included. Metabolic syndrome was defined using criteria of the IDF. In all patients spirometry, body composition, functional exercise performance, and mood and health status were assessed. Groups were stratified for BMI and gender. RESULTS: Metabolic syndrome was present in 57% of the COPD patients and 40% of the healthy subjects. After stratification for BMI, presence of metabolic syndrome in patients with a BMI ≥25 kg/m2 was higher than in healthy peers. Patients with metabolic syndrome and a BMI

In COPD, matrix remodeling contributes to airflow limitation. Recent evidence suggests that next to fibroblasts, the process of epithelial-mesenchymal transition can contribute to matrix remodeling. CSE has been shown to induce EMT in lung epithelial cells, but the signaling mechanisms involved are largely unknown and subject of this study. EMT was assessed in A549 and BEAS2B cells stimulated with CSE by qPCR, Western blotting and immunofluorescence for epithelial and mesenchymal markers, as were collagen production, cell adhesion and barrier integrity as functional endpoints. Involvement of TGF-β and HIF1α signaling pathways were investigated. In addition, mouse models were used to examine the effects of CS on hypoxia signaling and of hypoxia per se on mesenchymal expression. CSE induced EMT characteristics in A549 and BEAS2B cells, evidenced by decreased expression of epithelial markers and a concomitant increase in mesenchymal marker expression after CSE exposure. Furthermore cells that underwent EMT showed increased production of collagen, decreased adhesion and disrupted barrier integrity. The induction of EMT was found to be independent of TGF-β signaling. On the contrary, CS was able to induce hypoxic signaling in A549 and BEAS2B cells as well as in mice lung tissue. Importantly, HIF1α knock-down prevented induction of mesenchymal markers, increased collagen production and decreased adhesion after CSE exposure, data that are in line with the observed induction of mesenchymal marker expression by hypoxia in vitro and in vivo. Together these data provide evidence that both bronchial and alveolar epithelial cells undergo a functional phenotypic shift in response to CSE exposure which can contribute to increased collagen deposition in COPD lungs. Moreover, HIF1α signaling appears to play an important role in this process.

BACKGROUND: Transcutaneous neuromuscular electrical stimulation (NMES) can be applied as a complementary intervention to regular exercise training programs. A distinction can be made between high-frequency (HF) NMES and low-frequency (LF) NMES. In order to increase understanding of the mechanisms of functional improvements following NMES, the purpose of this study was to systematically review changes in enzyme activity, muscle fiber type composition and muscle fiber size in human lower-limb skeletal muscles following only NMES. METHODS: Trials were collected up to march 2012 and were identified by searching the Medline/PubMed, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL and The Physical Therapy Evidence Database (PEDro) databases and reference lists. 18 trials were reviewed in detail: 8 trials studied changes in enzyme activities, 7 trials studied changes in muscle fiber type composition and 14 trials studied changes in muscle fiber size following NMES. RESULTS: The methodological quality generally was poor, and the heterogeneity in study design, study population, NMES features and outcome parameters prohibited the use of meta-analysis. Most of the LF-NMES studies reported significant increases in oxidative enzyme activity, while the results concerning changes in muscle fiber composition and muscle size were conflicting. HF-NMES significantly increased muscle size in 50% of the studies. CONCLUSION: NMES seems to be a training modality resulting in changes in oxidative enzyme activity, skeletal muscle fiber type and skeletal muscle fiber size. However, considering the small sample sizes, the variance in study populations, the non-randomized controlled study designs, the variance in primary outcomes, and the large heterogeneity in NMES protocols, it is difficult to draw definitive conclusions about the effects of stimulation frequencies on muscular changes.

BackgroundPatients with COPD use a higher proportion of their peak aerobic capacity during the performance of domestic activities of daily life (ADLs) compared to healthy peers, accompanied by a higher degree of task-related symptoms. To date, the influence of body mass index (BMI) on the task-related metabolic demands remains unknown in patients with COPD. Therefore, the aim of our study was to determine the effects of BMI on metabolic load during the performance of 5 consecutive domestic ADLs in patients with COPD.MethodologyNinety-four COPD patients and 20 healhty peers performed 5 consecutive, self-paced domestic ADLs putting on socks, shoes and vest; folding 8 towels; putting away groceries; washing up 4 dishes, cups and saucers; and sweeping the floor for 4 min. Task-related oxygen uptake and ventilation were assessed using a mobile oxycon, while Borg scores were used to assess task-related dyspnea and fatigue.Principal findings1. Relative task-related oxygen uptake after the performance of domestic ADLs was increased in patients with COPD compared to healthy elderly, whereas absolute oxygen uptake is similar between groups; 2. Relative oxygen uptake and oxygen uptake per kilogram fat-free mass were comparable between BMI groups; and 3. Borg symptom scores for dyspnea en fatigue were comparable between BMI groups.ConclusionPatients with COPD in different BMI groups perform self-paced domestic ADLs at the same relative metabolic load, accompanied by comparable Borg symptom scores for dyspnea and fatigue.

BackgroundTo date, detailed analyses of walking patterns using accelerometers during the 6-min walk test (6MWT) have not been performed in patients with chronic obstructive pulmonary disease (COPD). Therefore, it remains unclear whether and to what extent COPD patients have an altered walking pattern during the 6MWT compared to healthy elderly subjects.Methodology/principal findings79 COPD patients and 24 healthy elderly subjects performed the 6MWT wearing an accelerometer attached to the trunk. The accelerometer features (walking intensity, cadence, and walking variability) and subject characteristics were assessed and compared between groups. Moreover, associations were sought with 6-min walk distance (6MWD) using multiple ordinary least squares (OLS) regression models. COPD patients walked with a significantly lower walking intensity, lower cadence and increased walking variability compared to healthy subjects. Walking intensity and height were the only two significant determinants of 6MWD in healthy subjects, explaining 85% of the variance in 6MWD. In COPD patients also age, cadence, walking variability measures and their interactions were included were significant determinants of 6MWD (total variance in 6MWD explained: 88%).Conclusions/significanceCOPD patients have an altered walking pattern during 6MWT compared to healthy subjects. These differences in walking pattern partially explain the lower 6MWD in patients with COPD.

Glutaredoxins (Grx) are redox enzymes that remove glutathione bound to protein thiols, know as S-glutathionylation (PSSG). PSSG is a reservoir of GSH and can affect the function of proteins. It inhibits the NF-κB pathway and LPS aspiration in Grx1 KO mice with decreased inflammatory cytokine levels. In this study we investigated whether absence of Grx1 similarly repressed cigarette smoke-induced inflammation in an exposure model in mice. Cigarette smoke exposure for four weeks decreased lung PSSG levels, but increased PSSG in lavaged cells and lavage fluid (BALF). Grx1 KO mice had increased levels of PSSG in lung tissue, BALF and BAL cells in response to smoke compared to wt mice. Importantly, levels of multiple inflammatory mediators in the BALF were decreased in Grx1 KO animals following cigarette smoke exposure compared to wt mice, as were levels of neutrophils, dendritic cells and lymphocytes. On the other hand, macrophage numbers were higher in Grx1 KO mice in response to smoke. Although cigarette smoke in vivo caused inverse effects in inflammatory and resident cells with respect to PSSG, primary macrophages and epithelial cells cultured from Grx1 KO mice both produced less KC compared to cells isolated from WT mice after smoke extract exposure. In this manuscript, we provide evidence that Grx1 has an important role in regulating cigarette smoke-induced lung inflammation which seems to diverge from its effects on total PSSG. Secondly, these data expose the differential effect of cigarette smoke on PSSG in inflammatory versus resident lung cells.

The objective of the present study was to determine the association between CT phenotypes—emphysema by low attenuation area and bronchitis by airway wall thickness—and body composition parameters in a large cohort of subjects with and without COPD. In 452 COPD subjects and 459 subjects without COPD, CT scans were performed to determine emphysema (%LAA), airway wall thickness (AWT-Pi10), and lung mass. Muscle wasting based on FFMI was assessed by bioelectrical impedance. In both the men and women with COPD, FFMI was negatively associated with %LAA. FMI was positively associated with AWT-Pi10 in both subjects with and without COPD. Among the subjects with muscle wasting, the percentage emphysema was high, but the predictive value was moderate. In conclusion, the present study strengthens the hypothesis that the subgroup of COPD cases with muscle wasting have emphysema. Airway wall thickness is positively associated with fat mass index in both subjects with and without COPD.